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Molecular and Functional Characterization of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP-38)/Vasoactive Intestinal Polypeptide Receptors in Pancreatic ß-Cells and Effects of PACAP-38 on Components of the Insulin Secretory System¹

Laboratory of Molecular Medicine, Department of Internal Medicine, University of Rome Tor Vergata (P.B., O.P., D.P., S.C., R.M., M.F., G.S., D.L., L.N.J.L.M.), 00133 Rome, Italy; the Institute of Bioimaging and Pathophysiology of the Central Nervous System, National Research Council (V.D., S.C.), Catania 95100, Italy; and the Institute of Experimental Medicine, National Research Council (L.N.J.L.M.), Rome 00133, Italy

Address all correspondence and requests for reprints to: Patrizia Borboni, M.D., Department of Internal Medicine, University of Rome Tor Vergata, Via di Tor Vergata 135, 00133 Rome, Italy. E-mail: borboni{at}uniroma2.it

It has been previously demonstrated that pituitary adenylate cyclase-activating polypeptide (PACAP) regulates insulin secretion. PACAP exerts its biological action by binding to at least three different receptor subtypes coupled to different signal transduction mechanisms. The signaling pathways underlying the insulinotropic effect of PACAP involve mainly the activation of adenylate cyclase to form cAMP, which directly and indirectly, through increased intracellular Ca⁺², stimulates insulin exocytosis. In the present study we have characterized the functional and molecular expression of PACAP/vasoactive intestinal polypeptide receptors isoforms and subtypes and its isoforms in a ß-cell line and in isolated rat pancreatic islets. Although insulinoma cells express the messenger RNA encoding PAC1 (-R and -hop variants), VPAC1 and VPAC2, binding experiments indicate the preponderance of PAC1 over VPAC1–2 receptors. We have also shown that the main signaling pathway of PACAP in ß-cells is mediated by adenylate cyclase, whereas the inositol 1,4,5-trisphosphate pathway is almost inactive. Furthermore, we have demonstrated that PACAP exerts long-term effects on ß-cells, such as transcriptional regulation of the insulin gene and genes of the glucose-sensing system (GLUT1 and hexokinase 1).

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